SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells

Abstract

Germline RB1 mutations strongly predispose humans to cone-precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRβ2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor suppressive TRβ1. TRβ2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In RB1-wild type neuroblastoma cells, endogenous Rb or ectopic TRβ2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRβ1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRβ2 counteracts TRβ1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies.

A novel thyroid hormone receptor isoform, TRβ2-46, promotes SKP2 expression and retinoblastoma cell proliferation

“…4 and 12 and data not shown). Impaired proliferation was associated with diminished SKP2 expression and impaired S-phase entry and was partially rescued by ectopic SKP2, indicating that SKP2 is an important TR␤2 target (12).…”

“…This RNA is predicted to encode a polypeptide of 54.4 kDa (UniProt P10828, isoform ␤2). We previously found that transduction of RB177 cells with TR␤2 cDNA containing the same open reading frame mainly increased expression of TR␤2-54, based on its comigration with the major endogenous TR␤2 species (12). Thus, we sought to define the origin of the smaller TR␤2-46.…”

“…TR␤2 is highly expressed in a limited number of cell types, including cone photoreceptor precursors, pituicytes, and cochlear hair cells (7)(8)(9), each of which aberrantly proliferates in response to RB loss (2,10,11). Indeed, TR␤2 is required for proliferation of retinoblastoma cells and enhances growth of Rb1-null mouse pituitary tumors, whereas ectopic TR␤2 enabled proliferation of RB-depleted neuroblastoma cells (12). TR␤2 appears to promote RB-deficient human retinoblastoma as well as Rb-deficient mouse pituitary tumors by antagonizing the highly related, more widely expressed, and tumor-suppressive thyroid hormone receptor TR␤1 (12,13).…”

“…Indeed, TR␤2 is required for proliferation of retinoblastoma cells and enhances growth of Rb1-null mouse pituitary tumors, whereas ectopic TR␤2 enabled proliferation of RB-depleted neuroblastoma cells (12). TR␤2 appears to promote RB-deficient human retinoblastoma as well as Rb-deficient mouse pituitary tumors by antagonizing the highly related, more widely expressed, and tumor-suppressive thyroid hormone receptor TR␤1 (12,13). TR␤2 and TR␤1 are produced from the same THRB gene but use alternative transcriptional promoters and N-terminal coding exons (8,14).…”

“…Additionally, TR␤1 can inhibit PI 3-kinase signaling (19,20) and was found to suppress liver and mammary tumors via induction of the NCoR transcriptional corepressor (21). Meanwhile, TR␤2 was found to oppose a TR␤1-dependent downregulation of the F-box protein SKP2 (12), which is required for production of RB-deficient tumors (22,23). However, it is unclear how TR␤2 opposes TR␤1 to enhance SKP2 expression and cell proliferation.…”